Lp(a): Evidence of a Link to Major Adverse Cardiovascular Events

Despite its recognition as a highly prevalent and genetically determined causal risk factor for cardiovascular disease (CVD), relatively few investigations have been aimed at tying lipoprotein(a) (Lp[a]) directly to an elevated risk of major adverse cardiovascular events (MACE) among individuals in various atherosclerotic cardiovascular disease (ASCVD) 10-year risk categories.^1,2 Benbow and colleagues aimed to address this existing void in Lp(a) research by examining the impact of increased Lp(a) levels on MACE across different categories of ASCVD risk.^2,3 Study findings were presented during a session titled “Increased Risk of MACE Attributed to Lipoprotein(a) Across Current Atherosclerotic Cardiovascular Disease Risk Categories,” during the American Heart Association Scientific Sessions 2023, which ran from November 11 to 13, 2023, in Philadelphia, Pennsylvania.³ Results of the study show a strong association between elevated Lp(a) increases and risk of MACE, independent of ASCVD risk score.

Link Between Lp(a) and Risk of MACE

For the retrospective, observational study, investigators examined a primary prevention cohort of White (n = 355,784) and Black (n = 6277) patients from the UK Biobank during 2006 to 2020 who had an existing Lp(a) measurement and no diagnosis of ASCVD prior to enrollment.^2,3 The study included a large population (N = 362,061) in whom circulating Lp(a) levels were measured; patients were categorized by Lp(a) level (eg, 105-150 nmol/L, 150-190 nmol/L, 190-215 nmol/L, and 215-260 nmol/L) and results were compared with those of patients with Lp(a) less than 105 nmol/L. The study population was nearly 55% female and the mean age of patients at the time of enrollment was 56.5 years.3 Approximately 98% of patients were classified as “White” and less than 2% of patients were classified as “Black” or “Black British.” Mean total cholesterol and triglycerides were approximately 222 mg/dL and 154 mg/dL, respectively, among the cohort. Patients had an average body mass index of 27 kg/m² and a mean systolic blood pressure of nearly 140 mm Hg. Across Lp(a) categories, incidence rates (IRs) of MACE and nonfatal myocardial infarction (MI) (evaluated as a component of MACE) were computed per 100 person-years.³ Associations between Lp(a) level and time until occurrence of first MACE and MI were analyzed using Cox proportional hazard models adjusted for age, sex, and ethnicity, with stratification based on ASCVD 10-year risk score categories (categorized as low, intermediate, and high risk).^2,3

Results showed that IRs of MACE and MI per 100 person-years increased corresponding with the patient’s 10-year ASCVD risk score.^2,3 However, a substantially significant increase was seen among those in the high-risk category (IRs, 1.52 and 0.75, respectively; n = 27,733) compared with the those in the intermediate- (IRs, 0.72 and 0.38; n = 121,272) and low-risk
(.14 and .09; n = 161,183) categories.³ Furthermore, within each risk category, Lp(a) levels exceeding 105 nmol/L were associated with an 82% increase in the IRs of MACE and MI.

Across and within all ASCVD 10-year risk categories, elevated Lp(a) (>105 nmol/L) was associated with a notable rise in the risk of both MACE and MI when compared with lower levels of Lp(a) (<105 nmol/L) as evidenced by adjusted hazard ratios (HRs). For patients in the low-risk category, HRs ranged from 1.15 to 1.55 for MACE and 1.32 to 1.72 for MI. For patients in the intermediate-risk category, HRs ranged from 1.19 to 1.51 for MACE and 1.37 to 1.77 for MI. Finally, for patients in the high-risk category, HRs ranged from 1.12 to 1.55 for MACE and 1.14 to 1.76 for MI.^2,3

Overall, higher Lp(a) levels (>105 nmol/L) were associated with a substantial increase in the risk of MACE (range, 12%-55%); and of MI (range, 14%-75%) when compared with levels below 105 nmol/L in this primary prevention population.³

Current Gaps in Knowledge and Study Limitations

Although Lp(a) is becoming more recognized as a risk factor for ASCVD, gaps in knowledge exist which must be addressed to further clinician understanding of its pathogenesis. For example, the causes of variation in plasma levels across different ethnicities are not fully understood. In addition, a complete understanding of apolipoprotein(a) synthesis, Lp(a) particle assembly, and the mechanism of clearance from circulation has not been achieved.⁴ The current study results provide insights on the observed impact of Lp(a) on MACE across ASCVD risk categories; however, certain limitations were acknowledged by the investigators. For instance, the applicability of the 10-year ASCVD risk calculator is restricted to patients of Black or White ethnicities, reducing the ability to generalize study design and results to other ethnicities. Also, the authors note the existence of healthy volunteer bias in the study population from the UK Biobank, further limiting generalizability.³

Spotlight on Screening of Lp(a)

Screening of Lp(a) levels is uncommon. It is not included in routine blood panels and thus the majority of patients are not screened.⁴ The results of a large observational study of 6 academic health systems in California from 2012 to 2021 revealed that only 0.3% of adults had been tested for Lp(a). Among patients with a personal or family history of CVD, Lp(a) testing was extremely low (< 4% and 3.3%, respectively).¹ The American College of Cardiology and American Heart Association guidelines recommend measurement of Lp(a) levels as a risk-enhancing factor for the primary prevention of ASCVD, especially if individuals have a known personal or family history of heart disease.^4,5 Nearly a quarter of people worldwide are estimated to have elevated Lp(a)—defined as greater than 50 mg/dL or 125 nmo/L.^1,5 Many of these patients are asymptomatic, remaining unaware of their condition.

Conclusions

Patients with elevated Lp(a) are at significantly higher risk of composite MACE and MI, regardless of their ASCVD 10-year risk score. In the study by Benbow et al, in all 3 ASCVD risk categories (low, intermediate, high), Lp(a) levels were the primary determinant of MACE or MI. Further understanding of its pathogenesis and awareness of Lp(a) levels is important to inform decision-making regarding treatment and risk management among clinicians. The underutilization of Lp(a) screening may be a missed opportunity to improve cardiovascular outcomes for patients. Screening of family members of individuals with elevated Lp(a) levels may also prove beneficial in identifying additional patients due to its genetic nature. Incorporating elevated Lp(a) levels into an individual’s ASCVD risk assessment during routine clinical practice could enhance risk predication and provide more informed guidance for follow-up disease management.

References

1. Bhatia HS, Hurst S, Desai P, Zhu W, Yeang C. Lipoprotein(a) testing trends in a large academic health system in the United States. J Am Heart Assoc. 2023;12(18):e031255. doi:10.1161/JAHA.123.031255
2. Benbow, H, Zabiby AA, Hu X, Byrne H, Costa-Scharplatz M. Abstract 14601. Increased risk of major adverse cardiovascular events attributed to lipoprotein(a) across current atherosclerotic cardiovascular disease risk categories. Circulation. 2023;148(suppl 1):A14601. doi:10.1161/circ.148.suppl_1.14601
3. Benbow, H, Zabiby AA, Hu X, Byrne H, Costa-Scharplatz M. Increased risk of major adverse cardiovascular events attributed to lipoprotein(a) across current atherosclerotic cardiovascular disease risk categories. Poster presented at: American Heart Association Scientific Sessions 2023; November 11-13, 2023; Philadelphia, PA. PR.AOS.549
4. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42(1):e48-e60. doi:10.1161/ATV.0000000000000147
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/AphA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625